1. Field of the Invention
The present invention relates to pharmaceutical compositions, particularly to the morpholinoethyl ester of mycophenolic acid and certain simple ester derivatives of the phenolic hydroxyl group, and to their use as immunosuppressive and anti-inflammatory agents. For example, they are useful for treating rheumatoid arthritis, in which there is an immunologically driven inflammatory process. Because of their effects on purine metabolism, the pharmaceutical compositions of the present invention also find use as anti-tumor, anti-viral and anti-psoriatic agents.
2. Cross-Reference to Related Applications
This application is related to Ser. No. 008,909 entitled "Heterocyclic Aminoalkyl Esters of Mycophenolic Acid and Derivatives Thereof," filed contemporaneously herewith; to Ser. No. 803,041, filed Nov. 27, 1985; and to Ser. No. 821,633, filed Jan. 23, 1986.
3. Background Information and Related Disclosures
Inflammatory diseases, in particular rheumatoid arthritis, have been treated with a variety of compounds representing several structural classes and biological activities, including, for example, anti-inflammatory agents (corticosteroids, aspirin, derivatives of arylacetic and arylpropionic acids, and oxicams), immunosuppressive agents and regimes (methotrexate, cyclophosphamide, cyclosporin, and total lymphoid irradiation), and long-acting anti-rheumatic drugs (gold salts, and penicillamine and its derivatives). However, no representative of any of these classes of compounds is regarded as ideal.
Mycophenolic acid is a weakly-active antibiotic found in the fermentation broth of Penicillium brevicompactum. Some compounds relating to mycophenolic acid, and their uses in the treatment of inflammatory diseases, such as rheumatoid arthritis, are disclosed in the following two prior related applications.
Ser. No. 803,041, filed Nov. 27, 1985, relates to compounds having the general structure of Formula 1: ##STR2## and the pharmaceutically acceptable salts thereof, where: R.sub.1 is H or lower alkyl having 1 to 6 carbon atoms;
R.sub.2 is H, lower alkyl having 1 to 6 carbon atoms or -phenyl-4-CO.sub.2 R.sub.3, in which R.sub.3 is H, lower alkyl having 1 to 6 carbon atoms or a pharmaceutically acceptable cation; PA0 R.sub.4 and R.sub.5 are each independently H or lower alkyl having 1 to 6 carbon atoms; PA0 X.sub.1 and Y.sub.1 are each independently O or S; and PA0 q is an integer of 1-6. PA0 R.sub.1 is selected from the group consisting of: ##STR4## in which: A.sub.1 is oxygen or sulfur; PA0 Q and Q.sub.1 are independently H or --CO.sub.2 R.sub.3 ; and PA0 Z.sub.1 is selected from the group consisting of: IH-tetrazolyl, --CH.sub.2 OH, --CHO, --CN, --C(O)A.sub.2 R.sub.6 and --C(O)NR.sub.7 R.sub.8, in which: PA0 (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; PA0 (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or PA0 (iii) relieving the disease, that is, causing the regression of clinical symptoms. PA0 morpholinoethyl E-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4- methyl-4-hexenoate; PA0 morpholinoethyl E-6-(1,3-dihydro-4-propionyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl )-4-methyl-4-hexenoate; PA0 morpholinoethyl E-6-(1,3-dihydro-4-pivaloyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4-hexenoate; and PA0 morpholinoethyl E-6-(1,3-dihydro-4-benzoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoate. PA0 an E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoyl halide, is condensed with morpholinoethanol to give a compound according to Formula A where Z is hydrogen; PA0 an E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoic acid is contacted with morpholinoethanol in the presence of a carbodiimide to give a compound according to Formula A where Z is hydrogen; PA0 an E-6-(1,3-dihydro-4-acyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoyl halide, is condensed with morpholinoethanol to give a compound according to Formula A where Z is --C(O)R; PA0 an E-6-(1,3-dihydro-4-acyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoic acid is condensed with morpholinoethanol in the presence of a carbodiimide to give a compound according to Formula A where Z is --C(O)R; PA0 morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoate is condensed with an acyl halide or anhydride to give a compound according to Formula A where Z is --C(O)R; PA0 contacting a pharmaceutically acceptable acid with a compound of Formula A to form the corresponding acid addition salt of Formula A; PA0 substituting a pharmaceutically acceptable acid salt of Formula A with another pharmaceutically acceptable acid; and PA0 contacting an acid addition salt of Formula A with a base to form the corresponding free base compounds of Formula A.
Ser. No. 821,633, filed Jan. 23, 1986, relates to compounds having the general structure of Formula 2: ##STR3## and the pharmaceutically acceptable salts thereof, where: A is oxygen or sulfur;
q is an integer from 0-6; PA1 R.sub.2 is alkyl, haloalkyl or --NR.sub.4 R.sub.5, where: PA1 R.sub.3 is H, alkyl or a pharmaceutically acceptable cation; PA1 A.sub.2 is oxygen or sulfur; PA1 R.sub.6 is H, alkyl, alkenyl, cycloalkyl, optionally substituted phenyl, optionally substituted benzyl or a pharmaceutically acceptable cation; and PA1 R.sub.7 and R.sub.8 are independently H, alkyl or cycloalkyl, or R.sub.7 and R.sub.8 taken together are --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --, --(CH.sub.2).sub.4 --, or --(CH.sub.2).sub.5 --; PA1 the compound of Formula A where Z is --C(O)R and wherein R is methyl is named "morpholinoethyl E-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoate" and PA1 the compound of Formula A where Z is --C(O)R and wherein R is phenyl is named "morpholinoethyl E-6-(1,3-dihydro-4-benzoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoate."
R.sub.4 and R.sub.5 are independently H, alkyl, haloalkyl, cycloalkyl, phenyl optionally monosubstituted with halogen, hydroxy, carboxy, chlorocarbonyl, sulfonylamino, nitro, cyano, phenyl, alkyl, acyl, alkoxycarbonyl, acylamino, dialkylamino or dialkylaminoethoxycarbonyl, phenyl optionally disubstituted with hydroxy, carboxy, nitro or alkyl, or benzyl optionally substituted with dialkylamino;
with the proviso that R.sub.1 and R.sub.6 cannot both be H if A and A.sub.2 are oxygen.
Compounds somewhat structurally similar to the compounds of Formulae 1 and 2 are described in U.S. Pat. Nos. 3,705,894; 3,853,919; 3,868,454; 3,880,995, in Japanese Pat. No. J 57024380, in J. Antibiot., 29(3), 275-85, 286-91 (1976), and in Cancer Research, 36(8), 2923-7 (1976). The disclosed compounds are described as having anti-tumor, immunosuppressive, anti-viral, anti-arthritic and/or anti-psoriastic activities.